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Invitae Study Finds Germline Risk Variants in Wide Range of Prostate Cancer Patients

NEW YORK – Germline cancer risk variants may turn up in more than 10 percent of prostate cancer cases across disease stages, according to early data presented from Invitae's Detect Hereditary Prostate Cancer (DHPC) program, hinting that there may be a benefit to doing germline genetic testing more broadly in these patients.

Current guidelines recommend germline assessments in men who have metastatic or aggressive disease, or a family history of cancer.

"If we rely only on testing men who we know meet [current germline testing] criteria, we'll miss men who have very clinically relevant germline pathogenic variants, but don't meet the specific criteria," explained Sarah Nielsen, a licensed certified genetic counselor within Invitae's medical affairs team, who presented results from the prostate cancer germline analysis in a talk posted online in the American College of Medical Genetics and Genomics virtual meeting on Friday.

As part of the ongoing DHPC, Nielsen and her colleagues assessed deidentified panel sequence data spanning between 47 and 87 genes for more than 2,200 men with prostate cancer who were offered hereditary testing free of charge as part of the sponsored program, searching for pathogenic or likely pathogenic germline variants. They also took note of risk alleles in lower penetrance variants in genes such as HOXB13 or APC.

The participants included men with low-, intermediate-, or high-risk localized prostate cancer, along with stage IIa prostate cancer patients who were no older than 55 years of age, and prostate cancer patients with tumors classified as stage IIb or above, Nielsen noted.

"Although the inclusion criteria look complicated, they're actually designed to be as broad as possible," she explained. "The only men who are not yet eligible are those with stage I or very low-risk disease over the age of 55."

Within the broader program, a patient's clinician would be informed when relevant germline variants are identified, allowing for related trial participation or targeted treatment. For example, the analyses suggested that some 71 percent of the germline variants found in the patients were clinically actionable, meaning they would be expected to prompt management or treatment changes or allow patients to participate in a clinical trial.

"Now, more than ever, understanding the underlying genetics of prostate cancer is important, because it can aid in treatment decisions through targeted therapies [and] clinical trial eligibility," she explained, "and of course additional management recommendations, both for the patient and their family members." The results may be particularly meaningful for female relatives, she added, "because we know many of the genes that cause prostate cancer also increase the risk for cancers like breast or ovarian cancer."

Studies done over the past five years or so have unearthed pathogenic germline variants in some 12 percent to 17 percent of men with prostate cancer, Nielsen noted, explaining that such alterations can impact everything from the treatment options available to them, to the management strategies used for other members of the same family.

"Genetic testing in prostate cancer is still relatively new, so we have a lot of work to do to catch up," she said, "but these data suggest that prostate cancer might even overshadow breast cancer in the proportion that is inherited."

Even so, past research has focused on specific subsets of prostate cancer patients with either more advanced disease or with a family or personal history of cancer that prompted a referral for genetic testing. This paradigm, Nielsen noted, has made it difficult to discern how common cancer-related germline variants may be across unselected prostate cancer patients at different disease stages.

The National Comprehensive Cancer Network's hereditary cancer testing guidelines, revised earlier this year, call for germline testing for men with metastatic or intraductal forms of prostate cancer or prostate cancer patients with high-grade disease and a risky family or personal history, including Ashkenazi Jewish ancestry.

But that guidance is somewhat at odds with the NCCN's specific testing recommendations specifically for prostate cancer, which include family history details that may be difficult to come by, Nielsen noted.

"The recommendations in these two sets of guidelines are somewhat discordant," she said. "They're also really tedious and cumbersome, which make them hard for clinicians to implement in practice and know who to test."

Based on data for 2,252 prostate cancer patients who ranged in age from 31 to 99 years old when they were tested between July of 2019 and January of this year, the investigators identified pathogenic or likely pathogenic variants in 271 of the men with prostate cancer and intermediate risk alleles in 31 of the patients.

The team was able to incorporate risk or cancer staging clues for more than 1,800 of the study participants, including more than 300 patients with African-American ancestry, 78 Hispanic patients, and 29 patients of Asian descent, though Nielsen noted that the clinical details returned on test forms varied significantly from one participant to the next.

More than half of the patients who shared sufficient clinical information for classifying tumor risk or stage had very high-risk, stage III or stage IV tumors, Nielsen reported, and the team tracked down informative germline variants in 13.5 percent of the 1,056 patients in that group.

But pathogenic, likely pathogenic, and lower risk variants turned up in a significant proportion of the other prostate cancer patients as well. In 228 patients with high-risk, stage III disease, the panel tests uncovered germline risk variants in 14 percent of cases, while such inherited risk variants turned up in 12.6 percent of the patients with intermediate- or low-risk stage II forms of prostate cancer.

"Historically it's been thought that men with metastatic or very high-risk disease have the highest pathogenic rate, which is why NCCN guidelines recommend testing for all metastatic patients but have many caveats for testing other prostate cancer patients," Nielsen said.

In the DHPC patients profiled so far, she noted that germline risk variants were most often detected in individuals with Ashkenazi Jewish ancestry, followed by Hispanic and Caucasian patients, while germline variants were found far less frequently in patients with African-American or Asian ancestry.

Such findings may be partly due to the smaller subsets of patients enrolled in the project from these populations. Nielsen cautioned, however, that there is still more work needed to find and characterize the inherited variants that can contribute to prostate cancer risk in different ethnic groups.

Together, the results hint that "broader testing criteria and greater access to testing lead to better informed care for patients and their families, especially for those from under-represented populations," Nielsen and her co-authors concluded.

At the ACMG annual meeting in Seattle last year, Invitae's Edward Esplin presented data on germline variants that could be found in patients from several cancer types, including prostate cancer, using an expanded germline panel sequencing approach.